3-10142097-G-C

Position:

• chr3-10142097-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.250G>C​(p.Val84Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.11

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 5) in uniprot entity VHL_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 3-10142097-G-C is Pathogenic according to our data. Variant chr3-10142097-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 229860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142097-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.250G>C	p.Val84Leu	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.250G>C	p.Val84Leu	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.250G>C	p.Val84Leu	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.320G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.250G>C	p.Val84Leu	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS1+PS4_Supporting+PM6+PS3+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2016	Variant summary: This c.250G>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Leu in beta domain of VHL protein. 2/4 in-silico tools predict this variant to be damaging. This variant was not found in approximately 99326 chromosomes from ExAC. This variant has been reported in one VHL patient as a de novo occurrence (Leonardi_2011) and in other two VHL patients as somatic occurrence (Burnichon_2011, Pena-Llopis_2013). Another nucleotide change c.250G>T leading to the same amino acid change is a known pathogenic variant, strongly supporting that this nucleotide change is also pathogenic. Functional studies show that p.V84L mutant impairs in forming stable pVHL-ElonginC-ElonginB (VCB) complexes which is implicated in the disease (Knauth_2009). Taken together, this variant has been classified as a Pathogenic. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 11331612, 11331613, 12510195, 19228690, 19602254, 21791076). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 229860). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 8592333, 11409863, 16502427, 19215943, 19270817, 25078357). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Leu). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2015

The p.V84L pathogenic mutation (also known as c.250G>C and p.V155L), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 250. The valine at codon 84 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in apparent de novo transmission in one individual with pheochromocytoma, out of a cohort of 426 unrelated individuals presenting with clinical suspicion for VHL (Leonardi E et al. Ann. Hum. Genet. 2011 Jul; 75(4):483-96). Additionally, a well described mutation at the same position (c.250G>T), also resulting in the valine at codon 84 being replaced by leucine, has been identified in a number of families with early-onset pheochromocytomas (VHL type 2C) (Crossey PA et al. J. Med. Genet.1995 Nov; 32(11):885-6; Abbott MA et al. Am. J. Med. Genet. A 2006 Apr; 140(7):685-90). Based on the available evidence, p.V84L is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0080	.;D
Sift4G	Uncertain	0.018	D;T
Polyphen		0.017	B;B
Vest4		0.68
MutPred		0.94		Loss of MoRF binding (P = 0.1081);Loss of MoRF binding (P = 0.1081);
MVP		1.0
MPC		0.56
ClinPred		0.98	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5030827; hg19: chr3-10183781; COSMIC: COSV56552062; COSMIC: COSV56552062;